Neonatal lupus erythematosus as a rare trigger of gastrointestinal involvement in neonates

Cutaneous and cardiac involvement in neonatal lupus erythematosus (NLE) has been extensively studied; however, gastrointestinal system involvement (GSI) remains unexplored. This study aimed to investigate the clinical features of GSI in patients with NLE with a particular focus on feeding intolerance (FI) and diarrhea. We conducted a retrospective analysis of the clinical data of patients diagnosed with NLE at the Children’s Hospital of Soochow University between 2011 and 2022. In this study, of 39 patients diagnosed with NLE, 27 presented with GSI. 9 patients who presented with FI or diarrhea as the primary manifestation were positive for anti-SSA antibody, and 5 were dual positive for anti-SSA and anti-SSB antibodies. Among the mothers of the NLE patients with GSI, 18 had systemic lupus erythematosus, 3 had Sjogren’s syndrome, 2 had mixed connective tissue disease, and one each had autoantibody abnormalities and photosensitivity symptoms; 4 mothers denied having any autoimmune disease. In this study, 69.23% of patients with NLE exhibited GSI, which was linked to hypocomplementemia and anti-SSA antibodies. Thus, clinicians should remain vigilant for NLE in neonates, particularly when accompanied with rash and other organ dysfunction and when the high-risk factors of FI and diarrhea have been excluded.

disorders.In some cases of recurrent FI/diarrhea, genetic metabolic disorders were excluded via blood and urine tandem mass spectrometry tests.
Data on the following parameters were collected from the patients' medical records: demographic data, clinical characteristics, laboratory parameters, imaging findings, and history of maternal rheumatic disease.Laboratory tests included routine hematological and biochemical parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin; serological tests for immune rheumatoid factors; complement factors; cerebrospinal fluid analysis; electroencephalography; and electrocardiography.In addition, data were collected from various diagnostic imaging modalities, including X-ray examination (abdominal and pulmonary), magnetic resonance imaging (cranial), computed tomography (abdominal, pulmonary, and cranial), ultrasonography (abdominal and cranial), and echocardiography.

Ethics statement
This study has already obtained an approval from the Ethics Committee of the Children's Hospital of Soochow University (Ethics Approval Number: 2023CS024).The parents of all infants willingly agreed to participate in the study, and for clinical data disclosure, they provided written informed consent.All experiments involving the included human research participants were performed in accordance with the Declaration of Helsinki.
Statistical analysis was performed using the SPSS 26.0 software.Categorical data are presented as frequency (percentage).The pairwise comparisons of categorical variables were performed using Fisher's exact test.

Patients with NLE presenting with FI/diarrhea
9 patients presented with FI (n = 7) or diarrhea (n = 2; Table 2).The 7 patients with FI included two with diarrhea, 5 with rash, 5 with liver involvement, 4 with hematologic involvement, 3 with neurological involvement, and 2 with cardiac involvement.3 of the 4 patients with diarrhea presented with rash, 3 had liver involvement, 2 had hematological involvement, and 1 had cardiac involvement.All 9 patients were positive for anti-SSA antibodies, whereas 5 were positive for both anti-SSA and anti-SSB antibodies.Of the 9 mothers, 4 had systemic lupus erythematosus (SLE), 2 had Sjogren's syndrome, 1 had mixed connective tissue disease (MTCD), and 2 denied having a history of any autoimmune disease.None of the 9 patients had any pre-existing lesions of the digestive system or coinfection with serious illnesses and all were negative for enteropathogenic tests.Complete blood and urine analyses along with genetic testing for metabolic screening were performed only in one case with transient

Follow-up
In general, follow-up data were obtained during outpatient visits or via telephone calls.A total of 28 cases were followed up.At the age of 2 months, 1 patient presented with a worsened generalized rash and mild liver function impairment.However, after steroid hormone treatment, the rash improved and completely resolved by the time the patient turned 5 months old.At the age of 9 months, all 28 infants showed normal blood indices and liver

Discussion
NLE is a neonatal condition caused by the transplacental transmission of maternal antibodies, which can lead to multiorgan damage in the fetus/newborn.The main antibodies involved in NLE are anti-SSA and anti-SSB 5 .The incidence of NLE in offspring born to mothers with anti-SSA and anti-SSB antibodies has been reported as approximately 2%.Of these, < 5% of patients with NLE progress to SLE during adolescence or adulthood 9 .
Earlier studies reported a higher risk of NLE development among females.However, subsequent studies revealed an equivalent risk among males and females 9,10 .In the present study, no significant sex difference was noted in patients with NLE.Multiorgan involvement in NLE is characterized by the reversible impairment of the cutaneous, hematological, and gastrointestinal systems and partially irreversible blockade of cardiac electrical conduction.Among  www.nature.com/scientificreports/these manifestations, cutaneous and hematological manifestations are more common 5,[11][12][13] .Clinical studies on gastrointestinal involvement in patients with NLE are relatively scarce.In the current study, organ involvement in the 39 patients with NLE, including 27 with concomitant GSI, was most commonly manifested as cutaneous and hematological involvement.The prevalence of cutaneous, hematological, and neurological involvement was higher in NLE patients with GSI than in those without GSI.Although the prevalence of cardiac involvement was lower in NLE patients with GSI than in those without, the difference was not statistically significant.Compared to patients with NLE but without GSI, a higher proportion of those with GSI had anemia, hypocomplementemia, neutropenia/deficiency, thrombocytopenia, and hypoalbuminemia, in terms of hematological manifestations.However, the differences were statistically significant only in the case of hypocomplementemia.Xu et al. reported that decreased C3 and CH50 levels are the independent risk factors of SLE combined with GSI 14 .Neurological involvement in NLE is rare, with cerebral edema being the most frequently reported manifestation.Few studies have also reported macrocephaly, stroke, and aseptic meningitis 6,15,16 .In the present study, neurological manifestations were intracranial hemorrhage, seizures, cerebral edema, widened extra-axial spaces, and aseptic meningitis.Of note, cerebral edema, widened extra-axial spaces, and aseptic meningitis were noted in patients with GSI; however, this association may have resulted from the small sample size.
Most studies have noted that the common symptoms of NLE are rash and cardiac arrhythmias 5,6 .However, in the current study, apart from rash and cardiac arrhythmias, additional gastrointestinal symptoms, including FI, diarrhea, and ascites, were observed in some patients.This co-occurrence may be attributed to mesenteric vasculitis caused by lupus antibodies and hepatic dysfunction 17,18 .SLE affects the entire gastrointestinal system, including the stomach, intestines, liver, and pancreas, all of which are directly or indirectly associated with SLE 18 .GSI in SLE can occur early or late in the course of the disease.In their study, Bader-Meuner et al. 19 reported that 17% of adolescent patients with SLE initially presented with gastrointestinal symptoms.Fawzy et al. 20 found that 42.5% of pediatric patients with SLE had concurrent GSI.In the present study, 27 (69.23%)patients with NLE had GSI, with 12 (30.77%)having gastrointestinal symptoms at initial presentation.15 (38.46%) of these patients developed gastrointestinal symptoms after diagnosis, which is a rate significantly higher than that reported in previous studies.This high rate may be related to the immature development of the neonatal gastrointestinal system, abundant intestinal mucosal vasculature, and weaker mucosal barrier, making neonates more susceptible to the effects of lupus antibodies.Oral ulcers caused by SLE are relatively rare and typically present as painless ulcers that are often located on the hard palate 21 .In the present study, only one patient had a painless oral ulcer on the hard palate, which resolved spontaneously after approximately 2 weeks.
To date, no specific antibodies have been directly associated with GSI in SLE 22 .Sönmez et al. 23 revealed that ENA may be associated with GSI in adolescent patients with SLE.In the present study, the positivity rate of anti-SSA antibodies in patients with NLE and GSI was significantly greater than that in those without GSI, suggesting a potential association between anti-SSA and GSI in these patients.Most mothers of patients with NLE have autoimmune diseases, including SLE, although a small portion of mothers may not have any history of autoimmune diseases 24,25 .In the current study, the most common autoimmune disorder among the mothers of the included patients was SLE, followed by Sjogren's syndrome, MTCD, photosensitivity symptoms, and autoantibody abnormalities.Seven mothers denied having any autoimmune diseases.Therefore, when newborns present with multiple organ involvement resembling NLE, they should be carefully evaluated, particularly for NLE, even if their mothers have no relevant history of autoimmune diseases or are negative for autoantibodies such as anti-SSA/SSB antibodies.Of note, both Sjogren's syndrome and MTCD occurred in the mothers of patients with NLE and GSI, suggesting a potential association between these conditions and GSI in NLE.
The present study assessed the clinical characteristics, antibody epidemiology, and maternal history of autoimmune diseases in patients with NLE and GSI and provided relevant insights that can guide future research.However, this study has some limitations.First, this was a single-center study with a relatively small sample size, which may have introduced bias in the research conclusions.Second, neonatal conjugated hyperbilirubinemia is a common occurrence, and it remains uncertain whether all cases can be attributed to NLE.This uncertainty may have impacted the validity of the results.Third, this study was retrospective and all children did not undergo comprehensive or dynamic monitoring with abdominal and neuroimaging examinations, possibly introducing bias in the results.Therefore, in the future, multicenter, collaborative, prospective studies are warranted for more reliable data that can provide appropriate guidance for the clinical diagnosis and treatment of NLE.

Conclusions
In summary, 69.23% of patients with NLE in this study had GSI, and GSI was associated with the presence of hypocomplementemia and anti-SSA antibodies.Some patients had gastrointestinal symptoms, including FI and diarrhea, at initial presentation.Therefore, clinicians should be alert to the possibility of NLE when patients present with gastrointestinal-related phenotypes during the neonatal and infancy period, particularly when they are accompanied by a rash or dysfunction of other organ systems.Moreover, other causes of these symptoms should be excluded via detailed inquiry regarding the maternal history of autoimmune diseases and timely autoantibody testing, particularly anti-SSA/SSB antibodies.

Table 1 .
Demographic information and presenting symptoms of NLE patients with GSI (n = 27).NLE neonatal lupus erythematosus, GSI gastrointestinal involvement.

Table 4 .
Epidemiology of antibodies and maternal diagnosis in NLE patients with GSI.NLE neonatal lupus erythematosus, GSI gastrointestinal involvement, SLE systemic lupus erythematosus, MTCD mixed connective tissue disease.